DOOR syndrome (or DOORS syndrome) genetics

In this post, I will describe one of my main research projects, the study of DOOR syndrome, or DOORS syndrome, which stands for :
– Deafness (sensorineural)
– Onychodystrophy (abnormal nails)
– Osteodystrophy (abnormal bones, especially in the digits)
– Retardation, mental (now know as intellectual disability)
– Seizures

The acronym was first used by Cantwell in 1975, and over 35 cases have been described since then. Seizures, present in most patients with DOORS syndrome, occasionally occur with increasing frequency or severity and can be refractory to antiepileptic medication. The seizures are more often generalized tonic-clonic, but myoclonic, partial and absence seizures also occur. Small or absent nails and hypoplastic terminal phalanges are noted in most individuals. A triphalangeal thumb is present in one third of affected individuals. Increased 2-oxoglutaric acid is often found in the blood and urine in DOORS syndrome, but is not pathognomonic. Levels can fluctuate between normal values to very high values over time in the same patient and are not elevated in all affected individuals. As such, its absence cannot be used to exclude a diagnosis of DOORS syndrome. 2-oxoglutaric aciduria is found in several metabolic disorders, but rarely in association with dysmorphisms such as in DOORS syndrome.

In a large international collaborative study, we have enrolled 26 families with at least three of features making the acronym of this condition, in a study to identify its genetic basis. We have identified mutations in TBC1D24 in 9 families out of 18 families with all five features. TBC1D24 is a known epilepsy gene, and it thought to be involved in vesicular trafficking. Despite the identification of the gene, we still can’t explain the 2-oxoglutaric aciduria, but further studies are underway to better understand this condition, define the genetic defects in other families, and optimize therapy for the seizures.